1. Field of the Invention
The invention disclosed relates generally to the fields of cancer therapy. More particularly, it relates to the process of cancer cell differentiation into cells of reduced malignancy, or lacking of malignancy. More specifically, the invention pertains to the utilization of cord-blood and placentally derived stem cells for the stimulation of cancer cell differentiation.
2. Description of Related Art
In the field of cellular biology, the definition of “stem cell” is dependent on function more than on morphology. The characteristic function of a stem cell is the ability to both self-renew and to differentiate. Stem cells differentiate upon need of the host in response to a wide variety of stimuli, these include the need for increased erythrocytes due to high altitude, or the need for augmented numbers of neutrophils in response to a bacterial infection [1]. Additionally, stem cells can be artificially induced to replicate through various means including administration of cytokines, growth factors, and small peptides [2]. A wide variety of tissue-specific stem cells have been identified, these include liver [3], skin [4], renal [5], pancreatic [6], gastric [7] and neuronal [8].
There are many similarities between neoplastically transformed tissue and stem cells in the sense that both express embryonic-like features, including the ability to migrate (metastasize), ability to suppress immune responses, and ability to proliferate. The sole difference resides in the fact that stem cells are highly regulated in terms of growth and differentiation, whereas cancer cells are not. At the molecular level, the more aggressive a cancer is, the more de-differentiated and “stem cell-like” it becomes. Specifically, regions of DNA that are transcriptionally silenced in mature tissue, become active when the tissue turns cancerous. For example the enzyme telomerase is needed for cells to escape proliferative senescence (ie multiple past the Hayflick limit). Stem cells possess active telomerase, in similarity to cancer cells. In contrast, as cells differentiate into specialized tissue, telomerase expression becomes silenced epigenetically through synergistic involvement of DNA methylation and histone deacetylation [9]. Conversely, tumor cells selectively silence, again through epigenetic mechanisms, genes that stop the tumor from being neoplastic. For example it is known that in prostate cancer tumor suppressor genes become silenced by methylation [10]. In fact, this is a common phenomena seen in a wide variety of histologically-differing tumors [11].
Stem cells actively secrete differentiation inducing factors, both known and unknown, that are capable of inducing epigenetic reprogramming in cells. In U.S. Patent Publication No. 2003/0211603 (Earp et al., hereby incorporated by reference in its entirety) disclose that embryonic stem cells possess the ability to reprogram differentiated cells to take a “de-differentiated” phenotype. Although the subject matter did not indicate potential application to cancer cells, such an application would be counterintuitive since more dedifferentiated tumors would be expected to possess increased malignancy. The invention disclosed in this patent is based on the unique and unanticipated discovery that such “reprogramming” of cancer cells does not lead to increased malignancy but instead induces a differentiation program which results in formation of normal, or normal-like progenitors.
Cord blood is a rich source of hematopoietic stem cells, capable of reconstituting the hematopoietic lineage in NOD-SCID mice. The potential utilization of cord blood stem cells, such as CD34+ cells, has led to the cryopreservation of such cells for more than a decade [12]. Indeed, the clinical use of cord blood derived stem cells is becoming increasing acceptable as an alternative to bone marrow transplant, or cytokine mobilized peripheral blood stem cell transplant for a wide variety of diseases. This is in part because of a reduced incidence of graft versus host reaction using cord blood stem cells in comparison with other sources [13]. Indeed, this was observed in pediatric leukemia patients lacking suitable major histocompatibility complex (MHC) matched donors [14], as well as in transplantation of patients with certain anemias or hematopoietic stem cell disorders such as beta-thalassemia major [15].
Placental extracts have also been previously described in the art. For example, a low molecular weight fraction of placental tissue is known to be immunosuppressive as reported by Chauaot. Additionally, the use of placenta in cosmetics is well known. Therefore, placenta and cord-blood are two accepted sources of biomaterial that is innocuous for human use.